Therapeutic polyesters and polyamides

ABSTRACT

Polymers (i.e. polyesters, polyamides, and polythioesters or a mixture thereof) which degrade hydrolytically into biologically active compounds are provided. Methods of producing these polymers, intermediates useful for preparing these polymers, and methods of using these polymers to deliver biologically active compounds to a host are also provided.

PRIORITY OF INVENTION

This application is a continuation of U.S. patent application Ser. No.10/753,048, filed 6 Jan. 2004, now abandoned which is a divisionalapplication of U.S. patent application Ser. No. 09/917,194, filed 27Jul. 2001, now U.S. Pat. No. 6,689,350; this application also claimspriority from U.S. Provisional Application No. 60/220,707, filed 27 Jul.2000 and U.S. Provisional Application No. 60/261,337, filed 12 Jan.2001.

BACKGROUND OF THE INVENTION

Polyesters are used routinely by those skilled in the art in variousdrug delivery systems.

For example, U.S. Pat. No. 5,942,252 describes a microcapsule comprisingas its biocompatible excipient a poly(lactide-co-glycolide),poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone,poly(lactide-co-caprolactone), poly(esteramide), polyorthoester,poly(p-hydroxybutyric) acid and/or polyanhydride for use in deliveringantigens or vaccines into and through mucosally-associated lymphoidtissue.

WO 99/29885 describes a process for degrading poly(ester-amides) andpoly(ester-urethanes) encapsulating chemicals, drugs, enzymes,microorganisms and seeds by introducing the polymer to an aqueousnutrient solution and inoculating the solution with a culture containinga selected bacteria.

WO 98/36013 describes aliphatic-aromatic dihydroxy compounds for use ascontrolled drug delivery systems.

WO 97/39738 describes preparation of microparticles of a sustainedrelease ionic conjugate comprising a free carboxyl group containingbiodegradable polymers and a free amino group-containing drug.

SUMMARY OF THE INVENTION

Polyesters, polythioesters, and polyamides which degrade into usefulbiologically active compounds have now been developed. Accordingly, theinvention provides a polymer of the invention which is polymercomprising a backbone, wherein the backbone comprises ester, thioester,or amide linkages, and wherein the backbone comprises one or more groupsthat will yield a biologically active compound upon hydrolysis of thepolymer.

The invention also provides a pharmaceutical composition comprising apolymer of the invention and a pharmaceutically acceptable carrier.

The invention also provides a therapeutic method for treating a diseasein an animal comprising administering to an animal in need of suchtherapy, an effective amount of a polymer of the invention.

The invention also provides a method of delivering a biologically activecompound to a host comprising administering to the host a biocompatibleand biodegradable polymer of the invention, which degrades into thebiologically active compound.

The invention provides a polymer of the invention for use in medicaltherapy, as well as the use of a polymer of the invention for themanufacture of a medicament useful for the treatment of a disease in amammal, such as a human.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing a polymer of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straightand branched groups; but reference to an individual radical such as“propyl” embraces only the straight chain radical, a branched chainisomer such as “isopropyl” being specifically referred to. Aryl denotesa phenyl radical or an ortho-fused bicyclic carbocyclic radical havingabout nine to ten ring atoms in which at least one ring is aromatic.Heteroaryl encompasses a radical attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms each selected from the groupconsisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absentor is H, O, (C₁-C₆)alkyl, phenyl or benzyl, as well as a radical of anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, or tetramethylene diradical thereto.

The term ester linkage means —OC(═O)— or —C(═O)O—; the term thioesterlinkage means —SC(═O)— or —C(═O)S—; and the term amide linkage means—N(R)C(═O)— or —C(═O)N(R)—, wherein each R is a suitable organicradical, such as, for example, hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl.

The term “amino acid,” comprises the residues of the natural amino acids(e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met,Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well asunnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also comprises natural and unnatural amino acids bearing aconventional amino protecting group (e.g. acetyl or benzyloxycarbonyl),as well as natural and unnatural amino acids protected at the carboxyterminus (e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide; or asan α-methylbenzyl amide). Other suitable amino and carboxy protectinggroups are known to those skilled in the art (See for example, Greene,T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis” secondedition, 1991, New York, John Wiley & sons, Inc., and references citedtherein).

The term “host” includes animals and plants.

The term “peptide” describes a sequence of 2 to 35 amino acids (e.g. asdefined hereinabove) or peptidyl residues. The sequence may be linear orcyclic. For example, a cyclic peptide can be prepared or may result fromthe formation of disulfide bridges between two cysteine residues in asequence. Preferably a peptide comprises 3 to 20, or 5 to 15 aminoacids. Peptide derivatives can be prepared as disclosed in U.S. Pat.Nos. 4,612,302; 4,853,371; and 4,684,620, or as described in theExamples hereinbelow. Peptide sequences specifically recited herein arewritten with the amino terminus on the left and the carboxy terminus onthe right.

Polymers of the Invention

The biocompatible, biodegradable polyesters, polythioesters, andpolyamides of the invention are useful in a variety of applicationswhere delivery of a biologically active compound is desired. Examples ofsuch applications include, but are not limited to, medical, dental andcosmetic uses.

The polymers of the invention may be prepared in accordance with methodscommonly employed in the field of synthetic polymers to produce avariety of useful products with valuable physical and chemicalproperties. The polymers can be readily processed into pastes or solventcast to yield films, coatings, microspheres and fibers with differentgeometric shapes for design of various medical implants, and may also beprocessed by compression molding and extrusion.

Polyesters and polyamides prepared in accordance with the presentinvention have average molecular weights of about 1500 Daltons up toabout 100,000 Daltons, calculated by Gel Permeation Chromatography (GPC)relative to narrow molecular weight polystyrene standards. Preferredpolyesters and polyamides have average molecular weights of about 1500Daltons, up to about 50,000 Daltons calculated by Gel PermeationChromatography (GPC) relative to narrow molecular weight polystyrenestandards. Preferred polyesters and polyamides have average molecularweights of about 1500 Daltons, up to about 35,000 Daltons.

Medical implant applications include the use of polyesters,polythioesters, or polyamides to form shaped articles such as vasculargrafts and stents, bone plates, sutures, implantable sensors,implantable drug delivery devices, stents for tissue regeneration, andother articles that decompose into non-toxic components within a knowntime period.

Polymers of the present invention can also be incorporated into oralformulations and into products such as skin moisturizers, cleansers,pads, plasters, lotions, creams, gels, ointments, solutions, shampoos,tanning products and lipsticks for topical application.

Although the invention provides homopolymers that are prepared fromsuitably functionalized biologically active compounds, Applicant hasdiscovered that the mechanical and hydrolytic properties of polymerscomprising one or more biologically active compounds can be controlledby incorporating a linking group (L) into the polymer backbone.

Preferably, the polymers of the invention comprise backbones whereinbiologically active compounds and linker groups are bonded togetherthrough ester linkages, thioester linkages, amide linkages, or a mixturethereof. Due to the presence of the ester, thioester, and/or amidelinkages, the polymers can be hydrolyzed under physiological conditionsto provide the biologically active compounds. Thus, the polymers of theinvention can be particularly useful as a controlled release source fora biologically active compound, or as a medium for the localizeddelivery of a biologically active compound to a selected site. Forexample, the polymers of the invention can be used for the localizeddelivery of a therapeutic agent to a selected site within the body of ahuman patient (i.e. within or near a tumor), where the degradation ofthe polymer provides localized, controlled, release of the therapeuticagent.

Biologically Active Compounds

The term “biologically active compound” includes therapeutic agents thatprovide a therapeutically desirable effect when administered to ananimal (e.g. a mammal, such as a human). Biologically active compoundsthat can be incorporated into the polymers of the invention possess atleast two functional groups that can each be incorporated into an ester,thioester, or amide linkage of a polymer (as discussed in detail below),such that, upon hydrolysis of the polymer, the therapeutic agent isobtained. These groups can independently be a hydroxy group (—OH), amercapto group (—SH), an amine group (—NHR), or a carboxylic acid(—COOH).

The biologically active compounds can also comprise other functionalgroups (including hydroxy groups, mercapto groups, amine groups, andcarboxylic acids, as well as others) that can be used to modify theproperties of the polymer (e.g. for branching, for cross linking, forappending other molecules (e.g. another biologically active compound) tothe polymer, for changing the solubility of the polymer, or foreffecting the biodistribution of the polymer). Lists of therapeuticagents can be found, for example, in: Physicians' Desk Reference, 55ed., 2001, Medical Economics Company, Inc., Montvale, N.J.; USPNDictionary of USAN and International Drug Names, 2000, The United StatesPharmacopeial Convention, Inc., Rockville, Md.; and The Merck Index, 12ed., 1996, Merck & Co., Inc., Whitehouse Station, N.J. One skilled inthe art can readily select therapeutic agents that possess the necessaryfunctional groups for incorporation into the polymers of the inventionfrom these lists.

Therapeutic agents that can be incorporated into the polymers of theinvention include suitably functionalized analgesics or general or localanesthetics, anti-convulsants, anti-diabetic agents, anti-fibroticagents, anti-infectives, anti-bacterials, anti-fungals,anti-neoplastics, cardioprotective agents, cardiovascular agents,anti-thrombotics, central nervous system stimulants, cholinesteraseinhibitors, contraceptives, deodorants, dopamine receptor agonists,erectile dysfunction agents, fertility agents, gastrointestinal agents,gout agents, hormones, immunomodulators, immunosuppressives, migraineagents, non-steroidal anti-inflammatory drugs (NSAIDs), motion sicknessagents, muscle relaxants, nucleoside analogs, neurodegenerative agents(e.g, Parkinson's disease), obesity agents, ophthalmic agents,osteoporosis agents, parasympatholytics, parasympathommetics,anti-anesthetics, prostaglandins, psychotherapeutic agents, respiratoryagents, sedatives, hypnotics, skin and mucous membrane agents, smokingsessation agents, sympatholytics, urinary tract agents, vaginal agents,and vasodilators (see Physicians' Desk Reference, 55 ed., 2001, MedicalEconomics Company, Inc., Montvale, N.J., pages 201-202).

Linking Group “L”

The nature of the linking group “L” in a polymer of the invention is notcritical provided the polymer of the invention possesses acceptablemechanical properties and release kinetics for the selected therapeuticapplication. The linking group L is typically a divalent organic radicalhaving a molecular weight of from about 25 daltons to about 400 daltons.More preferably, L has a molecular weight of from about 40 daltons toabout 200 daltons.

The linking group L typically has a length of from about 5 angstroms toabout 100 angstroms using standard bond lengths and angles. Morepreferably, the linking group L has a length of from about 10 angstromsto about 50 angstroms.

The linking group may be biologically inactive, or may itself possessbiological activity. The linking group can also comprise otherfunctional groups (including hydroxy groups, mercapto groups, aminegroups, carboxylic acids, as well as others) that can be used to modifythe properties of the polymer (e.g. for branching, for cross linking,for appending other molecules (e.g. another biologically activecompound) to the polymer, for changing the solubility of the polymer, orfor effecting the biodistribution of the polymer).

Specific and Preferred Values

Specific and preferred values listed herein for radicals, substituents,groups, and ranges, are for illustration only; they do not exclude otherdefined values or other values within defined ranges for the radicalsand substituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;(C₁-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; (C₁-C₆)alkylthio can be methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, orhexylthio; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl,indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl,triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or itsN-oxide) or quinolyl (or its N-oxide).

A specific biologically active compound that can be incorporated intothe polymers of the invention is atorvastatin; enalapril; ranitidine;ciprofloxacin; pravastatin; clarithromycin; cyclosporin; famotidine;leuprolide; acyclovir; paclitaxel; azithromycin; lamivudine; budesonide;albuterol; indinavir; metformin; alendronate; nizatidine; zidovudine;carboplatin; metoprolol; amoxicillin; diclofenac; lisinopril;ceftriaxone; captopril; salmeterol; xinafoate; imipenem; cilastatin;benazepril; cefaclor; ceftazidime; morphine; dopamine; bialamicol;fluvastatin; phenamidine; podophyllinic acid 2-ethylhydrazine;acriflavine; chloroazodin; arsphenamine; amicarbilide; aminoquinuride;quinapril; oxymorphone; buprenorphine; butorphanol; nalbuphine;streptozocin; doxorubicin; daunorubicin; plicamycin; idarubicin;mitomycin C; pentostatin; mitoxantrone; cytarabine; fludarabinephosphate; floxuridine; cladribine; 6-mercaptopurine; thioguanine;capecitabine; docetaxel; etoposide; gemcitabine; topotecan; vinorelbine;vincristine; vinblastine; teniposide; melphalan; methotrexate;2-p-sulfanilyanilinoethanol; 4,4′-sulfinyldianiline;4-sulfanilamidosalicylic acid; acediasulfone; acetosulfone; amikacin;amphotericin B; ampicillin; apalcillin; apicycline; apramycin;arbekacin; aspoxicillin; azidamfenicol; aztreonam; bacitracin;bambermycin(s); biapenem; brodimoprim; butirosin; capreomycin;carbenicillin; carbomycin; carumonam; cefadroxil; cefamandole;cefatrizine; cefbuperazone; cefclidin; cefdinir; cefditoren; cefepime;cefetamet; cefixime; cefmenoxime; cefminox; cefodizime; cefonicid;cefoperazone; ceforanide; cefotaxime; cefotetan; cefotiam; cefozopran;cefpimizole; cefpiramide; cefpirome; cefprozil; cefroxadine; cefteram;ceftibuten; cefuzonam; cephalexin; cephaloglycin; cephalosporin C;cephradine; chloramphenicol; chlortetracycline; clinafloxacin;clindamycin; clomocycline; colistin; cyclacillin; dapsone;demeclocycline; diathymosulfone; dibekacin; dihydrostreptomycin;dirithromycin; doxycycline; enoxacin; enviomycin; epicillin;erythromycin; flomoxef; fortimicin(s); gentamicin(s); glucosulfonesolasulfone; gramicidin S; gramicidin(s); grepafloxacin; guamecycline;hetacillin; isepamicin; josamycin; kanamycin(s); leucomycin(s);lincomycin; lomefloxacin; lucensomycin; lymecycline; meclocycline;meropenem; methacycline; micronomicin; midecamycin(s); minocycline;moxalactam; mupirocin; nadifloxacin; natamycin; neomycin; netilmicin;norfloxacin; oleandomycin; oxytetracycline; p-sulfanilylbenzylamine;panipenem; paromomycin; pazufloxacin; penicillin N; pipacycline;pipemidic acid; polymyxin; primycin; quinacillin; ribostamycin;rifamide; rifampin; rifamycin SV; rifapentine; rifaximin; ristocetin;ritipenem; rokitamycin; rolitetracycline; rosaramycin; roxithromycin;salazosulfadimidine; sancycline; sisomicin; sparfloxacin; spectinomycin;spiramycin; streptomycin; succisulfone; sulfachrysoidine; sulfaloxicacid; sulfamidochrysoidine; sulfanilic acid; sulfoxone; teicoplanin;temafloxacin; temocillin; tetroxoprim; thiamphenicol; thiazolsulfone;thiostrepton; ticarcillin; tigemonam; tobramycin; tosufloxacin;trimethoprim; trospectomycin; trovafloxacin; tuberactinomycin;vancomycin; azaserine; candicidin(s); chlorphenesin; dermostatin(s);filipin; flngichromin; mepartricin; nystatin; oligomycin(s); perimycinA; tubercidin; 6-azauridine; 6-diazo-5-oxo-L-norleucine;aclacinomycin(s); ancitabine; anthramycin; azacitadine; azaserine;bleomycin(s); carubicin; carzinophillin A; chlorozotocin;chromomycin(s); denopterin; doxifluridine; edatrexate; eflornithine;elliptinium; enocitabine; epirubicin; mannomustine; menogaril;mitobronitol; mitolactol; mopidamol; mycophenolic acid; nogalamycin;olivomycin(s); peplomycin; pirarubicin; piritrexim; prednimustine;procarbazine; pteropterin; puromycin; ranimustine; streptonigrin;thiamiprine; Tomudex®(N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-L-glutamicacid), trimetrexate, tubercidin, ubenimex, vindesine, zorubicin;argatroban; coumetarol; dicoumarol; ethyl biscoumacetate; ethylidenedicoumarol; iloprost; lamifiban; taprostene; tioclomarol; tirofiban;amiprilose; bucillamine; gusperimus; mycophenolic acid; procodazole;romurtide; sirolimus (rapamycin); tacrolimus; butethamine; fenalcomine;hydroxytetracaine; naepaine; orthocaine; piridocaine; salicyl alcohol;3-amino-4-hydroxybutyric acid; aceclofenac; alminoprofen; amfenac;bromfenac; bromosaligenin; bumadizon; carprofen; diclofenac; diflunisal;ditazol; enfenamic acid; etodolac; etofenamate; fendosal; fepradinol;flufenamic acid; gentisic acid; glucamethacin; glycol salicylate;meclofenamic acid; mefenamic acid; mesalamine; niflumic acid;olsalazine; oxaceprol; S-adenosylmethionine; salicylic acid; salsalate;sulfasalazine; or tolfenamic acid.

A preferred biologically active compound suitable for incorporation intopolyesters of the invention is morphine, dopamine, bialamicol, ortetracycline.

A preferred biologically active compound suitable for incorporation intopolyamides of the present invention is phenamidine, acriflavine,chloroazodin, arsphenamine, amicarbilide or aminoquinuride.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is oxymorphone, buprenorphine,butorphanol, or nalbuphine.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is methotrexate, doxorubicin, ordaunorubicin.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is atorvastatin, enalapril, ranitidine,pravastatin, cyclosporin, famotidine, leuprolide, acyclovir, lamivudine,budesonide, albuterol, indinavir, metformin, alendronate, nizatidine,zidovudine, carboplatin, metoprolol, lisinpril, captopril, salmeterol,cilastatin, benazepril, cefaclor, fluvastatin, quinapril, gemcitabine orvincristine.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is a nonsteroidal anti-inflammatorydrug, for example, a nonsteroidal anti-inflammatory drug as described inU.S. patent application (Ser. No. 09/732,516, filed 7 Dec. 2000),3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, amfenac,bromfenac, bromosaligenin, bumadizon, carprofen, diclofenac, diflunisal,ditazol, enfenamic acid, etodolac, etofenamate, fendosal, fepradinol,flufenamic acid, gentisic acid, glucamethacin, glycol salicylate,meclofenamic acid, mefenamic acid, mesalamine, niflumic acid,olsalazine, oxaceprol, S-adenosylmethionine, salicylic acid, salsalate,sulfasalazine, tolfenamic acid and the like.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is an anti-bacterial, for example,2-p-sulfanilyanilinoethanol, 4,4′-sulfinyldianiline,4-sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin,amoxicillin, amphotericin B, ampicillin, apalcillin, apicycline,apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin,aztreonam, bacitracin, bambermycin(s), biapenem, brodimoprim, butirosin,capreomycin, carbenicillin, carbomycin, carumonam, cefadroxil,cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir,cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefminox,cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan,cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil,cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam,cephalexin, cephaloglycin, cephalosporin C, cephradine, chloramphenicol,chlortetracycline, ciprofloxacin, clarithromycin, clinafloxacin,clindamycin, clomocycline, colistin, cyclacillin, dapsone,demeclocycline, diathymosulfone, dibekacin, dihydrostreptomycin,dirithromycin, doxycycline, enoxacin, enviomycin, epicillin,erythromycin, flomoxef, fortimicin(s), gentamicin(s), glucosulfonesolasulfone, gramicidin S, gramicidin(s), grepafloxacin, guamecycline,hetacillin, imipenem, isepamicin, josamycin, kanamycin(s),leucomycin(s), lincomycin, lomefloxacin, lucensomycin, lymecycline,meclocycline, meropenem, methacycline, micronomicin, midecamycin(s),minocycline, moxalactam, mupirocin, nadifloxacin, natamycin, neomycin,netilmicin, norfloxacin, oleandomycin, oxytetracycline,p-sulfanilylbenzylamine, panipenem, paromomycin, pazufloxacin,penicillin N, pipacycline, pipemidic acid, polymyxin, primycin,quinacillin, ribostamycin, rifamide, rifampin, rifamycin SV,rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin,rolitetracycline, rosaramycin, roxithromycin, salazosulfadimidine,sancycline, sisomicin, sparfloxacin, spectinomycin, spiramycin,streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid,sulfamidochrysoidine, sulfanilic acid, sulfoxone, teicoplanin,temafloxacin, temocillin, tetracycline, tetroxoprim, thiamphenicol,thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobramycin,tosufloxacin, trimethoprim, trospectomycin, trovafloxacin,tuberactinomycin, vancomycin and the like.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is an anti-fungal, for example,azaserine, candicidin(s), chlorphenesin, dermostatin(s), filipin,fungichromin, mepartricin, nystatin, oligomycin(s), perimycin A,tubercidin and the like.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is an anti-cancer (e.g., carcinomas,sarcomas, leukemias and cancers derived from cells of the nervoussystem), including anti-neoplastic, for example, 6-azauridine,6-diazo-5-oxo-L-norleucine, 6-mercaptopurine, aclacinomycin(s),ancitabine, anthramycin, azacitadine, azaserine, bleomycin(s),capecitabine, carubicin, carzinophillin A, chlorozotocin,chromomycin(s), cladribine, cytarabine, daunorubicin, denopterin,docetaxel, doxifluridine, doxorubicin, edatrexate, eflornithine,elliptinium, enocitabine, epirubicin, etoposide, floxuridine,fludarabine, gemcitabine, idarubicin, mannomustine, melphalan,menogaril, methotrexate, mitobronitol, mitolactol, mitomycin C,mitoxantrone, mopidamol, mycophenolic acid, nogalamycin, olivomycin(s),paclitaxel, pentostatin, peplomycin, pirarubicin, piritrexim,plicamycin, podophyllinic acid 2-ethylhydrazine, prednimustine,procarbazine, pteropterin, puromycin, ranimustine, streptonigrin,streptozocin, teniposide, thiamiprine, thioguanine, Tomudex®(N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-L-glutamicacid), toptecan, trimetrexate, tubercidin, ubenimex, vinblastine,vindesine, vinorelbine, zorubicin and the like.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is an anti-thrombotic, for example,argatroban, coumetarol, dicoumarol, ethyl biscoumacetate, ethylidenedicoumarol, iloprost, lamifiban, taprostene, tioclomarol, tirofiban andthe like.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is an immunosuppressive, for example,6-mercaptopurine, amiprilose, bucillamine, gusperimus, mycophenolicacid, procodazole, romurtide, sirolimus (rapamycin), tacrolimus,ubenimex and the like.

Another preferred biologically active compound that can be incorporatedinto a polymer of the invention is a general or local anesthetic, forexample, butethamine, fenalcomine, hydroxytetracaine, naepaine,orthocaine, piridocaine, salicyl alcohol and the like.

A specific value for L is a divalent, branched or unbranched, saturatedor unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wherein the chain isoptionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4)substituents selected from the group consisting of (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy.

Another specific value for L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbonatoms, wherein the chain is optionally substituted on carbon with one ormore (e.g. 1, 2, 3, or 4) substituents selected from the groupconsisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido,cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl,and heteroaryloxy.

Another specific value for L is an amino acid.

Another specific value for L is a peptide

Another specific value for L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—).

A more specific value for L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wherein the chain isoptionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4)substituents selected from the group consisting of (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.

Another more specific value for L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—).

Another more specific value for L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbonatoms.

Another more specific value for L is a divalent, branched or unbranched,hydrocarbon chain, having from 3 to 15 carbon atoms.

A preferred value for L is a divalent, branched or unbranched,hydrocarbon chain, having from 6 to 10 carbon atoms.

A more preferred value for L is a divalent hydrocarbon chain having 7,8, or 9 carbon atoms.

A most preferred value for L is a divalent hydrocarbon chain having 8carbon atoms.

A specific polymer of the invention comprises one or more units offormula (I):—R₁-A-L-A-  (I)wherein R₁ is group that will provide a biologically active compoundupon hydrolysis of the polymer; each A is independently an amidelinkage, a thioester linkage, or an ester linkage; and L is a linkinggroup.

Another specific polymer of the invention is a polymer which comprisesone or more units of formula (II) in the backbone:—R₂-A-L-A-R₃-A-L-A-  (II)wherein: R₂ and R₃ are each independently a group that will yield abiologically active compound upon hydrolysis of the polymer; each A isindependently an amide, thioester, or ester linkage; and each L isindependently a linking group. Such a polymer, wherein R₂ and R₃ aregroups that will yield differing biologically active compounds uponhydrolysis of the polymer, are particularly useful for theadministration of a combination of two therapeutic agents to an animal.

A preferred group of polyesters and polyamides includes polymers thatare comprised of compounds containing at least two free alcohol orphenol groups or two at least two free amine groups available forreactions which co-polymerize with carboxylic acid groups or bis(acyl)chlorides.

Formulations

The polymers of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally rectally, or parenterally, by intravenous,intramuscular, intraperitoneal, intraspinal, intracranial, topical orsubcutaneous routes. For some routes of administration, the polymer canconveniently be formulated as micronized particles.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparationspreferably contain at least 0.1% of polymer by weight. The percentage ofthe compositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 80% of the weight andpreferably 2 to about 60% of a given unit dosage form. The amount ofpolymer in such therapeutically useful compositions is such that aneffective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The polymer may also be administered intravenously, intraspinally,intracranially, or intraperitoneally by infusion or injection. Solutionsof the polymer can be prepared a suitable solvent such as an alcohol,optionally mixed with a nontoxic surfactant. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, triacetin, andmixtures thereof and in oils. Under ordinary conditions of storage anduse, these preparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile solutions or dispersions or sterile powders comprisingthe polymer containing the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the polymerin the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze drying techniques, which yield a powder of theactive ingredient plus any additional desired ingredient present in thepreviously sterile-filtered solutions.

For topical administration, the present polymers can be applied in pureform. However, it will generally be desirable to administer them ascompositions or formulations, in combination with a dermatologicallyacceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the polymers can be determined by comparing their invitro activity, and in vivo activity of the therapeutic agent in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949. Additionally, useful dosages can be determined bymeasuring the rate of hydrolysis for a given polymer under variousphysiological conditions. The amount of a polymer required for use intreatment will vary not only with the particular polymer selected butalso with the route of administration, the nature of the condition beingtreated and the age and condition of the patient and will be ultimatelyat the discretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

Combination Therapies

The polymers of the invention are also useful for administering acombination of therapeutic agents to an animal. Such a combinationtherapy can be carried out in the following ways: 1) a secondtherapeutic agent can be dispersed within the polymer matrix of apolymer of the invention, and can be released upon degradation of thepolymer; 2) a second therapeutic agent can be appended to a polymer ofthe invention (i.e. not in the backbone of the polymer) with bonds thathydrolyze to release the second therapeutic agent under physiologicalconditions; 3) the polymer of the invention can incorporate twotherapeutic agents into the polymer backbone (e.g. a polymer comprisingone or more units of formula (II)) or 4) two polymers of the invention,each with a different therapeutic agent can be administered together (orwithin a short period of time).

Thus, the invention also provides a pharmaceutical compositioncomprising a polymer of the invention and a second therapeutic agentthat is dispersed within the polymer matrix of a polymer of theinvention. The invention also provides a pharmaceutical compositioncomprising a polymer of the invention having a second therapeutic agentappended to the polymer (e.g. with bonds that will hydrolyze to releasethe second therapeutic agent under physiological conditions).

The polymers of the invention can also be administered in combinationwith other therapeutic agents that are effective to treat a givencondition to provide a combination therapy. Thus, the invention alsoprovides a method for treating a disease in a mammal comprisingadministering an effective amount of a combination of a polymer of theinvention and another therapeutic agent. The invention also provides apharmaceutical composition comprising a polymer of the invention,another therapeutic agent, and a pharmaceutically acceptable carrier.

Preferred drug combinations for incorporation into the polymers or thecompositions of the invention include the following:amoxicillin/clavulanic acid; and imipenem/cilastatin.

Preparation of Polymers of the Invention

Processes for preparing polymers of the invention are provided asfurther embodiments of the invention and are illustrated by thefollowing procedures in which the meanings of the generic radicals areas given above unless otherwise qualified.

For example, a polymer of the invention can be prepared, as illustratedin Scheme I, from a biologically active compound of formula (X₁—R₁—X₂)and a linker precursor of formula Z₁-L-Z₂, wherein X₁, X₂, Z₁, and Z₂are selected from the values in the table below.

The biologically active compound and the linker precursor can bepolymerized using well known synthetic techniques (e.g. by condensation)to provide a polymer of the invention (Ia) wherein each A isindependently an ester linkage, a thioester linkage, or an amidelinkage.

Depending on the reactive functional group (X₁ or X₂) of thebiologically active compound, a corresponding functional group (Z₁ orZ₂) can be selected from the following table, to provide an esterlinkage, thioester linkage, or amide linkage in the polymer backbone.

Functional Group On Biologically active Functional Group On compoundLinker Precursor Resulting Linkage In (X₁ or X₂) (Z₁ or Z₂) Polymer—COOH —OH Ester —COOH —NHR Amide —COOH —SH Thioester —OH —COOH Ester —SH—COOH Thioester —NHR —COOH Amide —SO₃H —OH Sulfate Ester —OH —SO₃HSulfate Ester

As will be clear to one skilled in the art, suitable protecting groupscan be used during the reaction illustrated in Scheme I (and in thereactions illustrated in Schemes II-XV below). For example, otherfunctional groups present in the biologically active compound or thelinker precursor can be protected during polymerization, and theprotecting groups can subsequently be removed to provide the polymer ofthe invention. Suitable protecting groups and methods for theirincorporation and removal are well known in the art (see for exampleGreene, T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis”second edition, 1991, New York, John Wiley & sons, Inc.).

Additionally, when a carboxylic acid is reacted with a hydroxy group, amercapto group, or an amine group to provide an ester linkage, thioesterlinkage, or an amide linkage, the carboxylic acid can be activated priorto the reaction, for example, by formation of the corresponding acidchloride. Numerous methods for activating carboxylic acids, and forpreparing ester linkages, thioester linkages, and amide linkages, areknown in the art (see for example Advanced Organic Chemistry: ReactionMechanisms and Structure, 4 ed., Jerry March, John Wiley & Sons, pages419-437 and 1281).

A polyester of the invention can be formed from a biologically activecompound of formula (HO—R₁—OH) and from a linker precursor of formulaHOOC-L-COOH as illustrated in Scheme II.

Reaction of the hydroxy groups of the biologically active compound withthe carboxylic acids of the linker precursor provides a polymer offormula (III), which is a polymer of the invention.

A preferred biologically active dihydroxy compound that can be used toprepare a polyester of the invention is: amikacin; amphotericin B;apicycline; apramycin; arbekacin; azidamfenicol; bambermycin(s);butirosin, carbomycin; cefpiramide; chloramphenicol; chlortetracycline;clindamycin; clomocycline; demeclocycline; diathymosulfone; dibekacin,dihydrostreptomycin; dirithromycin; doxycycline; erythromycin;fortimicin(s); gentamicin(s); glucosulfone solasulfone; guamecycline;isepamicin; josamycin; kanamycin(s); leucomycin(s); lincomycin;lucensomycin; lymecycline; meclocycline; methacycline; micronomicin;midecamycin(s); minocycline; mupirocin; natamycin; neomycin; netilmicin;oleandomycin; oxytetracycline; paromomycin; pipacycline; podophyllinicacid 2-ethylhydrazine; primycin; ribostamycin; rifamide; rifampin;rifamycin SV; rifapentine; rifaximin; ristocetin; rokitamycin;rolitetracycline; rosaramycin; roxithromycin; sancycline; sisomicin;spectinomycin; spiramycin; streptomycin; teicoplanin; tetracycline;thiamphenicol; thiostrepton; tobramycin; trospectomycin;tuberactinomycin; vancomycin; candicidin(s); chlorphenesin;dermostatin(s); filipin; fungichromin; mepartricin; nystatin;oligomycin(s); perimycin A; tubercidin; 6-azauridine; aclacinomycin(s);ancitabine; anthramycin; azacitadine; bleomycin(s); carubicin;carzinophillin A; chlorozotocin; chromomycin(s); doxifluridine;enocitabine; epirubicin; gemcitabine; mannomustine; menogaril;atorvastatin; pravastatin; clarithromycin; leuprolide; paclitaxel;mitobronitol; mitolactol; mopidamol; nogalamycin; olivomycin(s);peplomycin; pirarubicin; prednimustine; puromycin; ranimustine;tubercidin; vindesine; zorubicin; coumetarol; dicoumarol; ethylbiscoumacetate; ethylidene dicoumarol; iloprost; taprostene;tioclomarol; amiprilose; romurtide; sirolimus (rapamycin); tacrolimus;salicyl alcohol; bromosaligenin; ditazol; fepradinol; gentisic acid;glucamethacin; olsalazine; S-adenosylmethionine; azithromycin;salmeterol; budesonide; albuterol; indinavir; fluvastatin; streptozocin;doxorubicin; daunorubicin; plicamycin; idarubicin; pentostatin;mitoxantrone; cytarabine; fludarabine phosphate; floxuridine;cladribine; capecitabine; docetaxel; etoposide; topotecan; vinblastine;or teniposide.

A polyamide of the invention can be prepared using a procedure similarto that illustrated in Scheme II by replacing the biologically activedihydroxy compound in Scheme II with a suitable biologically activediamino compound. A preferred biologically active diamino compound thatcan be used to prepare a polymer of the invention is:2-p-sulfanilyanilinoethanol; 4,4′-sulfinyldianiline; acediasulfone;acetosulfone; amikacin; apramycin; arbekacin; bacitracin; brodimorprim;butirosin; colistin; capreomycin; dapsone; dibekacin; enviomycin;gramicidin S; polymyxin; teicoplanin; fortimicin(s); gentamicin(s);glucosulfone solasulfone; grepafloxacin; imipenem; isepamicin;kanamycin(s); lymecycline; micronomicin; neomycin; netilmicin;p-sulfanilylbenzylamine; paromomycin; ribostamycin; ristocetin;sisomicin; sparfloxacin; spectinomycin; sulfachrysoidine;sulfamidochrysoidine; sulfoxone; tetroxoprim; thiazolsulfone;tobramycin; trimethoprim; edatrexate; eflornithine; mannomustine;mitoxantrone; peplomycin; piritrexim; procarbazine; pteropterin;trimetrexate; gusperimus; butethamine; naepaine; piridocaine;trospectomycin; tuberactinomycin; vancomycin; candicidin(s);mepartricin; perimycin A; ranitidine; famotidine; metformin; nizatidine;carboplatin; lisinopril; methotrexate; mitomycin bleomycin(s) orthioguanine.

A polythioester of the invention can be prepared using a proceduresimilar to that illustrated in Scheme II by replacing the biologicallyactive dihydroxy compound in Scheme II with a suitable biologicallyactive dimercapto compound.

A polysulfate ester of the invention can be formed by replacing thedicarboxylic acid linker compound with a disulfo acid compound

A polyester/polyamide of the invention can be formed from a biologicallyactive compound of formula (HRN—R₁—OH) and from a linker precursor offormula HOOC-L-COOH as illustrated in Scheme III.

Reaction of the hydroxy group and the amino group of the biologicallyactive compound with the carboxylic acids of the linker precursorprovides a polymer of formula (IV), which is a polymer of the invention.

A preferred biologically active hydroxy/amino compound that can be usedto prepare a polyester/polyamide of the invention is:2-p-sulfanilyanilinoethanol; 4-sulfanilamidosalicylic acid; amikacin;amphotericin B; apramycin; arbekacin; aspoxicillin; butirosin;capreomycin; cefadroxil; cefatrizine; cefdinir; cefprozil; dibekacin;dihydrostreptomycin; dirithromycin; enviomycin; gramicidin(s);teicoplanin; fortimicin(s); gentamicin(s); glucosulfone solasulfone;isepamicin; kanamycin(s); lucensomycin; lymecycline; meropenem;micronomicin; natamycin; neomycin; netilmicin; paromomycin;ribostamycin; ristocetin; sisomicin; spectinomycin; streptomycin;thiostrepton; tobramycin; trospectomycin; tuberactinomycin; vancomycin;candicidin(s); mepartricin; nystatin; perimycin A; tubercidin;anthramycin; azacitadine; bleomycin(s); carubicin; carzinophillin A;cytarabine; denopterin; elliptinium; epirubicin; gemcitabine;mannomustine; peplomycin; pirarubicin; pteropterin; puromycin;streptonigrin; tubercidin; ubenimex; vindesine; zorubicin; gusperimus;ubenimex; fenalcomine; hydroxytetracaine; orthocaine;3-amino-4-hydroxybutyric acid; etofenamate; fepradinol; mesalamine;S-adenosylmethionine; leuprolide; acyclovir; paclitaxel; lamivudine;albuterol; indinavir; alendronate; zidovudine; metoprolol; amoxicillin;salmeterol; imipenem; doxorubicin; daunorubicin; idarubicin;pentostatin; mitoxantrone; fludarabine phosphate; floxuridine;cladribine; vinorelbine; vincristine; or vinblastine.

A polythioester/polyamide of the invention can be prepared using aprocedure similar to that illustrated in Scheme II by replacing thehydroxy/amino biologically active compound in Scheme II with a suitablemercapto/amino biologically active compound.

A polyamide of the invention can be formed from a biologically activecompound of formula (HOOC—R₁—COOH) and from a linker precursor offormula HRN-L-NRH as illustrated in Scheme IV.

Reaction of the carboxylic acid groups of the biologically activecompound with the amino groups of the linker precursor provides apolymer of formula (V), which is a polymer of the invention.

A preferred biologically active dicarboxylic acid compound that can beused to prepare a polyamide of the invention is: bambermycin(s);carbenicillin; carzinophillin A; cefixime; cefminox; cefpimizole;cefodizime; cefonicid; ceforanide; cefotetan; ceftibuten; cephalosporinC; denopterin; edatrexate; moxalactam; olsalazine; penicillin N;quinacillin; temocillin; ticarcillin; Tomudex®(N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-L-glutamicacid); lisinopril; cilastatin; ceftazidime; or methotrexate.

A polyester of the invention can be prepared using a procedure similarto that illustrated in Scheme IV by replacing the diamino linkerprecursor with a dihydroxy linker precursor. Similarly, apolyester/polyamide of the invention can be prepared using a proceduresimilar to that illustrated in Scheme IV by replacing the diamino linkerprecursor with an hydroxy/amino linker precursor; and apolythioester/polyamide of the invention can be prepared using aprocedure similar to that illustrated in Scheme IV by replacing thediamino linker precursor with an mercapto/amino linker precursor.

A polyester of the invention can be formed from a biologically activecompound of formula (HO—R₁—COOH) and from a linker precursor of formulaHO-L-COOH as illustrated in Scheme V.

Reaction of the hydroxy group and the carboxylic acid of thebiologically active compound, with the carboxylic acid and the hydroxygroup of the linker precursor provides a polymer of formula (VI), whichis a polymer of the invention.

A preferred biologically active hydroxy/carboxylic acid compound thatcan be used to prepare a polymer of the invention is:4-sulfanilamidosalicylic acid; amphotericin B; apalcillin; apicycline;aspoxicillin; bambermycin(s); biapenem; cefadroxil; cefamandole;cefatrizine; cefbuperazone; cefdinir; cefonicid; cefoperazone;cefpiramide; cefprozil; enviomycin; teicoplanin; flomoxef; glycolsalicylate; lucensomycin; lymecycline; meropenem; moxalactam; mupirocin;nadifloxacin; natamycin; panipenem; podophyllinic acid 2-ethylhydrazine;ritipenem; salazosulfadimidine; sulfaloxic acid; vancomycin;3-amino-4-hydroxybutyric acid; candicidin(s); carzinophillin A;denopterin; diflunisal; fendosal; gentisic acid; iloprost; lamifiban;mesalamine; nystatin; olsalazine; oxaceprol; pteropterin; romurtide;salicylic acid; salsalate; streptonigrin; sulfasalazine; taprostene;ubenimex; amoxicillin; pravastatin; imipenem; mycophenolic acid; orfluvastatin.

A polyester/polyamide of the invention can be prepared using a proceduresimilar to that illustrated in Scheme V by replacing biologically activehydroxy/carboxylic compound with a biologically active amino/carboxylicacid compound. A preferred biologically active amino/carboxylic acidcompound that can be used to prepare a polymer of the invention is:3-amino-4-hydroxybutyric acid; 4-sulfanilamidosalicylic acid;6-diazo-5-oxo-L-norleucine; aceclofenac; acediasulfone; alminoprofen;amfenac; amphotericin B; ampicillin; argatroban; aspoxicillin;azaserine; aztreonam; bromfenac; bumadizon; candicidin(s); carprofen;carumonam; carzinophillin A; cefadroxil; cefatrizine; cefclidin;cefdinir; cefditoren; cefepime; cefetamet; cefixime; cefmenoxime;cefminox; cefodizime; ceforanide; cefotaxime; cefotiam; cefozopran;cefpirome; cefprozil; cefroxadine; ceftazidime; cefteram; ceftibuten;ceftriaxone; cefuzonam; cephalexin; cephaloglycin; cephalosporin C;cephradine; clinafloxacin; cyclacillin; denopterin; edatrexate;eflornithine; enfenamic acid; enoxacin; epicillin; etodolac; enviomycin;teicoplanin; flufenamic acid; grepafloxacin, hetacillin; imipenem;lomefloxacin; lucensomycin; lymecycline; meclofenamic acid; mefenamicacid; meropenem; mesalamine; natamycin; niflumic acid; norfloxacin;nystatin; pazufloxacin; penicillin N; pipemidic acid; procodazole;pteropterin; S-adenosylmethionine; sparfloxacin; streptonigrin;succisulfone; sulfachrysoidine; temafloxacin; tigemonam; tirofiban;tolfenamic acid; tosufloxacin; trovafloxacin; ubenimex; vancomycin;enalapril; amoxicillin; ciprofloxacin; diclofenac; lisinopril;ceftriaxone; cilastatin; benazepril; cefaclor; ceftazidime; quinapril;melphalan; or methotrexate.

A polythioester/polyester of the invention can be prepared using aprocedure similar to that illustrated in Scheme V by replacingbiologically active hydroxy/carboxylic compound with a biologicallyactive mercapto/carboxylic acid compound. A preferred biologicallyactive mercapto/carboxylic acid compound that can be used to prepare apolymer of the invention is bucillamine or captopril.

A polysulfonamide of the invention can be prepared using a proceduresimilar that illustrated in Scheme V by replacing the biologicallyactive hydroxy/carboxylic compound with a biologically activeamine/sulfo acid compound. A preferred biologically active amine/sulfoacid compound that can be used to prepare a polymer of the invention is:sulfanilic acid or sulfoxone.

In the polymers of formulae (I, and III-VI) illustrated in Schemes I-Vabove, R₁, A, L, and R can have any of the values, specific values, orpreferred values described herein.

The co-polymerization of morphine with a diacid chloride to provide apolyester of the invention is depicted in Scheme VI.

In the reaction illustrated in Scheme VI, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (7) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (7), m is an integer that is greaterthan or equal to 2.

The co-polymerization of dopamine with bis(acyl) chloride to provide apolyester of the invention is depicted in Scheme VII.

In the reaction illustrated in Scheme VII, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (8) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (8), m is an integer that is greaterthan or equal to 2. Prior to the polymerization illustrated in SchemeVII, the amino group of dopamine can be protected with a suitableprotecting group, which can subsequently be removed, to provide thepolymer of the invention.

It should be noted that dopamine can also be incorporated into apolyester/polyamide of the invention by reacting the amino group andeither hydroxy group of dopamine with a compound of formula HOOC-L-COOH,or an activated derivative thereof to provide a compound of formula (21)or (22):

Prior to the polymerization, the hydroxy group which will not bepolymerized can be protected with a suitable protecting group, which cansubsequently be removed to provide the polymer of the invention.

The co-polymerization of acriflavine to provide a polyamide of theinvention is depicted in Scheme VIII.

The diamino groups of acriflavine are copolymerized in solution(preferably high-boiling point organic solvent such asdimethylformamide) with an activated dicarboxylic acid (e.g. sebacoylchloride). The polyamide is isolated by methods well known in the art.Alternatively, the amino groups can be reacted with a dicarboxylic acidby employing high temperatures (e.g. in the melting range), or acoupling agent. This process of making polyamides is also well known tothose skilled in the art. In yet another embodiment, the diamino groupscan be activated in the presence of hexamethylsilazine to form silylatedamines. The silylated amines can then be allowed to react with anactivated dicarboxylic acid (e.g. sebacyl chloride) to provide a polymerof the invention.

In the reaction illustrated in Scheme VIII, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (9) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (9), m is an integer that is greaterthan or equal to 2.

The preparation of a polymer of the invention comprising methotrexate isillustrated in Scheme IX.

In the reaction illustrated in Scheme IX, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (10) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (10), m is an integer that isgreater than or equal to 2. Prior to the polymerization illustrated inScheme IX, the carboxylic acids of methotrexate can be protected withsuitable protecting groups, which can subsequently be removed, toprovide the polymer of the invention.

It will be appreciated by one skilled in the art that a polymer of theinvention of the following formula (20):

wherein each A is independently an ester linkage, a thioester linkage,or an amide linkage can be prepared as illustrated in Scheme X byselecting a linker precursor with the appropriate functionality. For acompound of formula (20) the linking group L is preferably —(CH₂)_(x)—,and more preferably, L is —(CH₂)₈—. A polymer of formula (20) wherein Land each A has any of the values, specific values, or preferred valuesdescribed herein is a preferred polymer of the invention. For a polymerof formula (20), m is an integer that is greater than or equal to 2.

The preparation of another polymer of the invention comprisingmethotrexate is illustrated in Scheme X.

In the reaction illustrated in Scheme X, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (II) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (II), m is an integer that isgreater than or equal to 2. Prior to the polymerization illustrated inScheme X, the amino groups of methotrexate can be protected withsuitable protecting groups, which can subsequently be removed, toprovide the polymer of the invention.

The preparation of another polymer of the invention comprisingmethotrexate is illustrated in Scheme XI.

In the reaction illustrated in Scheme XI, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (12) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (12), m is an integer that isgreater than or equal to 2. Prior to the polymerization illustrated inScheme XI, the carboxylic acid and amino group of methotrexate that arenot reacted to form the polymer can be protected with suitableprotecting groups, which can subsequently be removed, to provide thepolymer of the invention.

A polymer of the invention that comprises methotrexate is particularlyuseful for treating psoriasis, inflammatory bowel disease, skin cancer,or brain tumors. Such a polymer is also particularly useful as ananti-neoplastic agent anti-infective agent, and for local administrationof an anti-tumor agent following a lumpectomy or mastectomy.

The preparation of a polymer of the invention comprising doxorubicin isillustrated in Scheme XII.

In the reaction illustrated in Scheme XII, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (13) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (13), m is an integer that isgreater than or equal to 2. Prior to the polymerization illustrated inScheme XII, the functional groups of doxorubicin that are not reacted toform the polymer can be protected with suitable protecting groups, whichcan subsequently be removed, to provide the polymer of the invention.

A polymer of the invention that comprises doxorubicin is particularlyuseful for local administration as an anti-tumor (e.g. brain tumor)agent or anti-neoplastic agent.

The preparation of a polymer of the invention comprising daunorubicin isillustrated in Scheme XIII.

In the reaction illustrated in Scheme XIII, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (14) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (14), m is an integer that isgreater than or equal to 2. Prior to the polymerization illustrated inScheme XIII, the functional groups of daunorubicin that are not reactedto form the polymer can be protected with suitable protecting groups,which can subsequently be removed, to provide the polymer of theinvention.

A polymer of the invention that comprises daunorubicin is particularlyuseful for local administration as an anti-tumor (e.g. brain tumor)agent or an anti-neoplastic agent.

The preparation of a polymer of the invention comprising5-aminosalicylic acid is illustrated in Scheme XIV.

In the reaction illustrated in Scheme XIV, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (15) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (15), m is an integer that isgreater than or equal to 2. Prior to the polymerization illustrated inScheme XIV, the carboxylic acid can be protected with a suitableprotecting group, which can subsequently be removed, to provide thepolymer of the invention.

5-Aminosalicilic acid can also be incorporated into a polymer of theinvention which is a polymer of formula (23) or (24):

The preparation of a polymer of the invention comprising mycophenolicacid is illustrated in Scheme XV.

In the reaction illustrated in Scheme XV, the linking group L ispreferably —(CH₂)_(x)—, and more preferably, L is —(CH₂)₈—. A polymer offormula (16) wherein L has any of the values, specific values, orpreferred values described herein is a preferred polymer of theinvention. For a polymer of formula (16), m is an integer that isgreater than or equal to 2.Activity

The ability of a polymer of the invention to produce a given therapeuticeffect can be determined using in vitro and in vivo pharmacologicalmodels which are well known to the art.

All publications, patents, and patent documents (including the entirecontents of U.S. Provisional Patent Application No. 60/220,707, filed 27Jul. 2000) are incorporated by reference herein, as though individuallyincorporated by reference. The invention has been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope of theinvention.

1. A polymer which comprises one or more units of formula (II) in thebackbone:—R₂-A-L-A-R₃-A-L-A-  (II) wherein R₂ and R₃ are each independently agroup that will yield an immunosuppressive upon hydrolysis of thepolymer; each A is independently an amide or ester linkage; and each Lis independently a linking group.
 2. The polymer of claim 1 wherein theimmunosuppressive is selected from 6-mercaptopurine, amiprilose,gusperimus, mycophenolic acid, procodazole, romurtide, sirolimus(rapamycin), tacrolimus, and ubenimex.
 3. The polymer of claim 1 whereinL is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or moreof the carbon atoms is optionally replaced by (—O—), and wherein thechain is optionally substituted on carbon with one or more (e.g. 1, 2,3, or 4) substituents selected from the group consisting of(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 4.The polymer of claim 1 wherein L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbonatoms, wherein the chain is optionally substituted on carbon with one ormore substituents selected from the group consisting of (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 5.The polymer of claim 1 wherein L is a peptide.
 6. The polymer of claim 1wherein L is an amino acid.
 7. The polymer of claim 1 wherein L is adivalent, branched or unbranched, saturated or unsaturated, hydrocarbonchain, having from 1 to 25 carbon atoms, wherein one or more of thecarbon atoms is optionally replaced by (—O—).
 8. The polymer of claim 1wherein L is a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms,wherein one or more of the carbon atoms is optionally replaced by (—O—),and wherein the chain is optionally substituted on carbon with one ormore (e.g. 1, 2, 3, or 4) substituents selected from the groupconsisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido,cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl,and heteroaryloxy.
 9. The polymer of claim 1 wherein L is a divalent,branched or unbranched, saturated or unsaturated, hydrocarbon chain,having from 3 to 15 carbon atoms, wherein one or more of the carbonatoms is optionally replaced by (—O—).
 10. The polymer of claim 1wherein L is a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms. 11.The polymer of claim 1 wherein L is a divalent, branched or unbranched,hydrocarbon chain, having from 3 to 15 carbon atoms.
 12. The polymer ofclaim 1 wherein L is a divalent, branched or unbranched, hydrocarbonchain, having from 6 to 10 carbon atoms.
 13. The polymer of claim 1wherein L is a divalent hydrocarbon chain having 7, 8, or 9 carbonatoms.
 14. The polymer of claim 1 wherein L is a divalent hydrocarbonchain having 8 carbon atoms.
 15. A pharmaceutical composition comprisinga polymer of claim 1 and a pharmaceutically acceptable carrier.
 16. Amethod for producing a polymer as described in claim 1 comprisingco-polymerizing an immunosuppressant containing at least two alcohol orphenol groups or at least two amine groups with carboxylic acid groupsor bis(acyl)chlorides.
 17. A method of delivering an immunosuppressiveto a host comprising administering to the host a polymer of claim 1.